Acta Med. Okayama, 2014
Vol. 68, No. 4, pp. 235ﾝ241
CopyrightⒸ 2014 by Okayama University Medical School.
http://escholarship.lib.okayama-u.ac.jp/amo/
Factors Associated with Remission and/or Regression of
Microalbuminuria in Type 2 Diabetes Mellitus
Tetsuichiro Onoa＊, Kenichi Shikataa,b, Mikako Obikac, Nobuyuki Miyataked,
Ryo Koderaa,b, Daisyo Hirotaa, Jun Wadaa, Hitomi Kataokaa,e,
Daisuke Ogawaf, and Hirofumi Makinoa
a
b
c
e
-
f
d
-
The aim of this study was to clarify the factors associated with the remission and/or regression of
microalbuminuria in Japanese patients with type 2 diabetes mellitus. We retrospectively analyzed the
data of 130 patients with type 2 diabetes mellitus with microalbuminuria for 2-6 years (3.39 ± 1.31
years). Remission was defined as improving from microalbuminuria to normoalbuminuria using the
albumin/creatinine ratio (ACR), and regression of microalbuminuria was defined as a decrease in
ACR of 50ｵ or more from baseline. Progression of microalbuminuria was defined as progressing
from microalbuminuria to overt proteinuria during the follow-up period. Among 130 patients with
type 2 diabetes mellitus with microalbuminuria, 57 and 13 patients were defined as having remission
and regression, respectively, while 26 patients progressed to overt proteinuria. Sex (female), higher
HDL cholesterol and lower HbA1c were determinant factors associated with remission/regression of
microalbuminuria by logistic regression analysis. Lower systolic blood pressure (SBP) was also correlated with remission/regression, but not at a significant level. These results suggest that proper
control of blood glucose, BP and lipid profiles may be associated with remission and/or regression of
type 2 diabetes mellitus with microalbuminuria in clinical practice.
Key words: microalbuminuria, type 2 diabetes mellitus, remission, regression
T
he number of diabetes mellitus patients is dramatically increasing in Japan and has become
public health challenge. It is well known that diabetic
nephropathy is one of the most serious complications
of diabetes mellitus. More than 300,000 patients in
Japan undergo hemodialysis, and about 44ｵ of those
just starting hemodialysis in 2012 were affected by
diabetes mellitus [1]. In addition, diabetic nephropaReceived January 24, 2014 ; accepted March 19, 2014.
Corresponding author. Phone :＋81ﾝ86ﾝ235ﾝ7235; Fax :＋81ﾝ86ﾝ222ﾝ5214
E-mail : [email protected] (T. Ono)
＊
thy is an independent risk factor for cardiovascular
disease, and has a serious impact on quality of life and
health care costs [2-7]. The earliest known manifestation of diabetic nephropathy is the presence of small
amounts of albumin in the urine, called microalbuminuria [8]. In our country, more than 40ｵ of
patients with type 2 diabetes mellitus have microalbuminuria [9]. Recommended treatment of diabetic
nephropathy is as follows: 1) tight control of blood
Conflict of Interest Disclosures: No potential conflict of interest relevant
to this article was reported.
236
Ono et al.
glucose, 2) tight control of blood pressure (BP), 3)
suppression of the renin-angiotensin system (RAS)
using angiotensin-converting-enzyme (ACE) inhibitors
or angiotensin-receptor blockers (ARBs), 4) control of
lipid profiles, 5) diet therapy, and 6) lifestyle modification (including smoking cessation) [9]. In patients
with type 2 diabetes mellitus, the course of renal
dysfunction is more heterogeneous, and the natural
progression less well characterized than in patients
with type 1 diabetic nephropathy [10]. Furthermore,
for a wide variety of treatment methods, the impact of
each treatment on preventing and improving diabetic
nephropathy in patients with type 2 diabetes mellitus
has not been fully examined in clinical practice.
In the present study, we evaluated the remission/
regression vs. progression of microalbuminuria in
Japanese patients with type 2 diabetes mellitus in a
single clinical practice. In addition, we clarified the
factors that are associated with remission and/or
regression of microalbuminuria.
Subjects and Methods
We retrospectively collected the data
of 130 subjects who met the following criteria: (1)
diagnosed as having type 2 diabetes mellitus in accordance with the criteria of the Japanese Diabetes
Society [11] and the World Health Organization [12]
at the Department of Medicine, Okayama University
Hospital between January 2006 and December 2009;
(2) having microalbuminuria by at least 2 measurements of albumin/creatinine ratio (ACR) in a spot
urine sample, and their diabetic nephropathy status
was determined; (3) having no complicating cancer,
liver disease, collagen disease, or nondiabetic kidney
disease confirmed by renal biopsy; and (4) having
received follow-up physical examinations at least every
two months, while undergoing measurements of ACR
in a spot urine sample at least once a year for 2-6
years.
All participants received treatment based on the
standard strategies for diabetes mellitus, hypertension, and dyslipidemia during these periods.
This study was approved by the Ethics Committee
on Epidemiological Studies of Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
Acta Med. Okayama　Vol. 68, No. 4
The albumin excretion rate was estimated on the basis
of the ACR in spot urine samples, as previously
described [13-15]. The levels of albumin excreted in
each measurement of ACR were classified as normoalbuminuria (ACR ＜ 30mg/g creatinine), microalbuminuria (30 ｦ ACR ＜ 300mg/g creatinine), and overt
proteinuria (ACR ｧ 300mg/g creatinine).
We applied the
criteria of previous reports for remission, regression
and progression of microalbuminuria [16, 17]. Remission of microalbuminuria was defined as returning to
normoalbuminuria during the follow-up period; regression of microalbuminuria was defined as a decrease in
ACR of 50ｵ or more from baseline. Otherwise,
progression of microalbuminuria was defined as progressing from microalbuminuria to overt proteinuria
during the follow-up period.
All data were retrospectively obtained from electronic charts. Body mass
index (BMI) was the weight in kilograms divided by
the square of the height in meters. The estimated
Glomerular Filtration Rate (eGFR) was calculated
using the following equation: eGFR (ml/min/1.73m2)
＝ 194 × Cr-1.094 × Age-0.287 × 0.739 (a constant derived
specifically for women) [18]. Among antihypertensive
drugs, RAS blockade drugs including ACE inhibitors
or ARBs and other antihypertensive drugs were separately recorded and analyzed.
Values are expressed as
means ± standard deviations (SDs) for continuous
variables. The participants were classified by the
course of microalbuminuria, remission and/or regression, no change and progression. One-way analysis of
variance (ANOVA) and Tukeyʼs test were used to
compare among 3 groups. Participants were also classified as being with or without remission/regression
of microalbuminuria during the follow-up period.
Comparisons between these 2 groups was performed
using Chi-squared tests for categorical variables and
unpaired tests for continuous variables. Univariate
and multivariate analyses were also performed using a
logistic regression model.
To investigate the importance of each clinical
practice recommendation, we dichotomized the levels
of HbA1c, BP, and lipid profiles as salutary or nonsalutary. The salutary levels were defined as follows:
HbA1c ＜ 6.5ｵ, BP ＜ 130/80mmHg, and lipid profiles
August 2014
Remission and/or Regression of Microalbuminuria
＜ 150mg/dl for triglycerides, ＜ 120mg/dl for LDL
cholesterol, and ｧ 40mg/dl for HDL cholesterol,
according to the clinical practice recommendations of
the Japanese Diabetes Society [19]. We then coded
each follow-up period of observation on a scale from 0
to 3 according to the number of the 3 factors with a
salutary level, and calculated hazard ratios.
All statistical analyses were performed using the
SPSS 21.0 software program for Windows. We
selected values ＜ 0.05 as the threshold of statistical
significance in all tests.
Results
During the follow-up period (average of 3.4 years),
among 130 type-2 diabetes mellitus patients with
microalbuminuria, 57 patients (43.8ｵ) demonstrated
remission of microalbuminuria, 13 patients (10.0ｵ)
237
demonstrated regression of microalbuminuria, and 26
patients (20.0ｵ) progressed to overt proteinuria. The
remission/regression rate was higher than that of
progression.
The clinical characteristics of the patients at baseline according to the course of microalbuminuria are
summarized in Table 1. Among participants with
remission and/or regression of microalbuminuria, the
proportions of males and alcohol drinkers were significantly lower than those in other categories. In
participants with progression of microalbuminuria,
systolic BP, ACR and diabetic retinopathy were significantly higher than those in other participants. In
participants with remission/regression of microalbuminuria, HDL cholesterol was significantly higher
than that in participants with progression of microalbuminuria.
Next, we compared the clinical characteristics
Table 1　Clinical characteristics of the study participants at baseline according to the course of microalbuminuria
Number of participants: n (%)
Male sex: n (%)
Age (years)
Duration of diabetes (years)
Current smoking: n (%)
Alcohol drinker: n (%)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
HbA1c (%)
Plasma glucose (mg/dl)
BUN (mg/dl)
Serum creatinine (mg/dl)
Estimated Glomerular Filtration Rate (ml/min/1.73m2)
ACR (mg/g creatinine)
Uric acid (mg/dl)
Total cholesterol (mg/dl)
Triglycerides (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
Diabetic neuropathy: n (%)
Diabetic retinopathy: n (%)
IHD: n (%)
CVD: n (%)
PAD: n (%)
Use of ACE inhibitor or ARBs: n (%)
Use of Statin: n (%)
Remission and/or Regression
No change
70 (53.8)
30 (42.9)ab
59.9 ± 14.3
9.6 ± 7.9
16 (27.6)
12 (20.7)ab
25.3 ± 4.5
128.9 ± 14.7b
74.7 ± 9.5
7.5 ± 1.4
168.0 ± 58.1
17.2 ± 8.5
0.81 ± 0.73
79.6 ± 28.0
69.6 ± 61.6b
5.2 ± 2.0
198.0 ± 34.1
147.4 ± 90.7
60.1 ± 15.9b
111.7 ± 28.6
26 (39.4)
23 (33.8)b
8 (11.4)
3 (4.3)
2 (2.9)
30 (42.9)
20 (28.6)
34 (26.2)
24 (70.6)
62.0 ± 13.8
10.7 ± 10.1
8 (27.6)
15 (50.0)
25.7 ± 4.7
132.1 ± 11.4b
74.9 ± 11.6
7.4 ± 1.0
181.5 ± 60.2
17.2 ± 6.6
0.86 ± 0.25
70.1 ± 20.3
79.0 ± 73.9b
5.6 ± 1.4
204.7 ± 31.8
178.9 ± 113.7
54.0 ± 16.1
117.3 ± 29.6
13 (40.6)
8 (25.8)b
4 (11.8)
2 (5.9)
2 (5.9)
18 (52.9)
12 (35.5)
Progression
26 (20.0)
20 (76.9)
64.3 ± 11.5
14.2 ± 11.2
12 (50.5)
11 (45.8)
24.6 ± 4.1
141.2 ± 15.9
79.0 ± 12.4
7.7 ± 1.5
178.2 ± 49.6
18.3 ± 4.9
0.88 ± 0.32
71.8 ± 25.2
152.9 ± 107.2
5.5 ± 1.4
184.1 ± 38.9
158.9 ± 157.8
50.4 ± 12.6
103.9 ± 24.9
15 (60.0)
16 (61.5)
4 (15.4)
2 (7.7)
1 (3.8)
16 (61.5)
6 (23.1)
Data are means ± SD unless otherwise indicated. IHD, ischemic heart disease. CVD, cerebral vascular disorder. PAD, peripheral arterial disease.
a
＜ 0.05 versus no change. b ＜ 0.05 versus progression.
238
Ono et al.
Acta Med. Okayama　Vol. 68, No. 4
between patients with and without remission/regression in the follow-up period. In the univariate analysis,
significant differences of plasma glucose, HbA1c,
creatinine and BUN were noted between the 2 groups
(Table 2). To adjust for confounding factors such as
duration of diabetes, total cholesterol and smoking
habits by logistic regression analysis, we found that
the female sex [odds ratio (OR): 4.34, (95ｵ confidence interval (CI): 1.70-11.12), ＝ 0.002], higher
HDL cholesterol ( ｧ 50mg/dl) [OR: 3.65, (95ｵ CI:
1.06-9.88), ＝ 0.031] and lower HbA1c ( ｦ 6.0ｵ)
[OR: 5.61, (95ｵ CI: 1.13-27.85), ＝ 0.035] were
independently associated with remission/regression of
microalbuminuria (Table 3), whereas lower SBP
( ｦ 130mmHg) [OR: 2.66, (95ｵ CI: 0.83-7.23), ＝
0.122] was weakly associated with remission/regression of microalbuminuria,
., not at a significant
level.
Table 2　Clinical characteristics of the study participants at follow-up according to the presence or absence of remission and/or regression of microalbuminuria
Remission and/or Regression
No Remission and/or Regression
2.8 ± 1.1
25.4 ± 4.3
129.3 ± 11.6
73.6 ± 9.1
6.7 ± 0.8
151.1 ± 32.2
16.3 ± 4.6
0.75 ± 0.20
71.4 ± 21.2
5.4 ± 1.3
190.5 ± 25.1
134.9 ± 71.4
55.6 ± 14.7
109.5 ± 19.9
39 (55.7)
24 (34.3)
4.1 ± 1.6
25.3 ± 4.4
131.1 ± 12.0
73.6 ± 11.0
7.2 ± 1.2
168.8 ± 52.4
18.7 ± 6.4
0.91 ± 0.29
64.9 ± 19.7
5.7 ± 1.3
192.2 ± 43.3
161.0 ± 117.9
51.6 ± 12.8
105.2 ± 22.1
41 (68.3)
31 (51.7)
Mean follow-up time (years)
Body mass index (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
HbA1c (%)
Plasma glucose (mg/dl)
BUN (mg/dl)
Serum creatinine (mg/dl)
Estimated Glomerular Filtration Rate (ml/min/1.73m2)
Uric acid (mg/dl)
Total cholesterol (mg/dl)
Triglycerides (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
Use of ACE inhibitor or ARBs: n (%)
Use of Statin: n (%)
Data are means ± SD unless otherwise indicated.
＊
value
＜0.001＊
0.893
0.398
0.991
0.023＊
0.028＊
0.020＊
＜0.001＊
0.079
0.215
0.793
0.131
0.117
0.254
0.153
0.074
＜ 0.05.
Table 3　The ORs of factors associated with the remisson and/or regression of microalbuminuria with the logistic regrsssion model
Factor
Sex (female)
HDL cholesterol (mg/dl)
HDL ＜ 40
40 ｦ HDL ＜ 50
50 ｦ HDL ＜ 60
60 ｦ HDL
HbA1c (%)
7.0 ＜ HbA1c
6.5 ＜ HbA1c ｦ 7.0
6.0 ＜ HbA1c ｦ 6.5
HbA1c ｦ 6.0
Systolic blood pressure (mmHg)
140 ＜ SBP
130 ＜ SBP ｦ 140
SBP ｦ 130
Adjusted odds ratio
95% confidence interval
4.34
1.70-11.12
1
1.10
3.65
4.17
ref.
0.23-3.06
1.06-9.88
1.20-11.53
1
3.53
4.26
5.61
ref.
0.67-18.63
0.83-21.92
1.13-27.85
1
1.42
2.66
ref.
0.51-3.76
0.83-7.23
value
0.002＊
0.031＊
0.035＊
0.122　The multivariate model was adjusted for BMI, duration of diabetes, total cholesterol, smoking habits, and use of ACE inhibitor or ARBs.
Ref., reference category. ＊ ＜0.05.
August 2014
Remission and/or Regression of Microalbuminuria
Finally, the clinical importance of recommended
guidelines for glycemic exposure, BP and lipid profiles was evaluated by the multivariate model adjusted
for sex and use of ACE inhibitor or ARBs. The hazard ratio for the remission/regression of microalbuminuria increased with each increment in the number
of factors at a salutary level (Fig. 1), when 3 factors,
as compared with none, were at the salutary levels,
the hazard ratio for remission/regression of microalbuminuria was 1.489 (95ｵ CI: 0.625-3.550), but not
at a significant level.
Discussion
Microalbuminuria in patients with type 2 diabetes
mellitus has been considered the first step toward
overt proteinuria and renal failure. However, our
results indicate that microalbuminuria can improve to
normal levels in some Japanese type 2 diabetes mellitus patients. Among 130 patients with microalbuminuria, only 20ｵ of patients progressed to overt proteinuria, whereas 40ｵ of patients improved to
normoalbuminuria.
Hazard ratio
2
1.5
1
0.5
0
0
1.000
1
2
No. of factors at salutary levels
3
1.182
1.286
1.489
(0.555 ﾝ 2.519) (0.578 ﾝ 2.862) (0.625 ﾝ 3.550)
Hazard ratio (95% confidence interval)
Fig. 1　Additive effects of factors at salutary levels on remission
and/or regression of microalbuminuria. Salutary levels of the various factors were defined as ＜ 6.5% for HbA1c, a combination of
＜ 130 mmHg of systolic blood pressure and ＜ 80 mmHg of diastolic
blood pressure, and a combination of ＜ 150 mg/dl of triglyceride,
＜ 120 mg/dl of LDL cholesterol, and ｧ 40 mg/dl of HDL cholesterol. The reference category was considered to be the absence of
a salutary level for any of the 3 factors. The estimates were
adjusted for sex, and use of ACE inhibitor or ARBs. The number of
patients having 0, 1, 2, and 3 factors at salutary levels were 23
(18.1%), 47 (37.0%), 40 (31.5%), and 17 (13.4%), respectively.
239
This study also provided evidence that rigorous
control of glycemic exposure, HDL cholesterol and
SBP, and female sex were independently associated
with the remission and/or regression of microalbuminuria. Improvement of microalbuminuria has recently
been reported in patients with type 1 and type 2 diabetes mellitus. Perkins
. found frequent regression, with 58ｵ (95ｵ CI: 52-64) incidence at the
6-year follow-up in patients with type 1 diabetes mellitus [16]. Araki
. also found frequent remission
and/or regression, with ～50ｵ incidence at the
6-year follow-up in patients with type 2 diabetes mellitus [17]. These observations strongly indicate that
microalbuminuria frequently regresses, contrary to
our expectations. In this study, we additionally identified the factors associated with the reduction of
microalbuminuria in type 2 diabetes mellitus.
The level of blood glucose seems to be the strongest factor influencing the onset of microalbuminuria.
This has been demonstrated in several observational
studies [13, 14, 20-23] as well as in clinical trials
[24-27]. In our study, the lower HbA1c ( ｦ 6.0ｵ)
was independently associated with remission/regression of microalbuminuria. This cutoff value is lower
than the recommended therapeutic target ( ＜ 7.0ｵ)
for HbA1c [19, 28]. Additionally, the Steno type 2
randomized study [29] showed that the target HbA1c
level to prevent progression of diabetic nephropathy
was ＜ 6.5ｵ. In our study, the ORs for remission/
regression of microalbuminuria in subjects with
HbA1c ＜ 7.0ｵ was not statistically significant (OR:
3.68, 95ｵ confidence interval: 0.71-17.33). Our
participantsʼ mean HbA1c at baseline (7.2 ± 1.0ｵ) was
lower than in other previous studies.
Essential hypertension [30-33], elevated SBP
[23, 32], cigarette smoking [14, 34], elevated levels of serum cholesterol and triglycerides [22], and
genetic susceptibility are risk factors for diabetic
nephropathy [35]. Maintaining BP ＜ 130/80mmHg
is recommended in diabetic patients for preservation
of renal function and reduction of cardiovascular events
[19, 28, 36]. In our study, lower SBP ( ｦ 130mmHg)
and lower DBP ( ｦ 80mmHg) were not independently
associated with remission/regression of microalbuminuria because our participantsʼ mean SBP and DBP
at baseline (130.6 ± 10.8mmHg, 75.3 ± 8.5mmHg) were
comparably well controlled. In lipid profiles, HDL
cholesterol was independently associated with
240
Ono et al.
improvement of microalbuminuria. We thought that
LDL cholesterol might not have been statistically
significant in our study because LDL cholesterol was
well controlled by the use of statins, especially in
participants with progression of microalbuminuria.
These results suggest that normalization of the lipid
profile may be associated with remission/regression of
type 2 diabetes mellitus with microalbuminuria.
Sex is one of the risk factors for microvascular
complications, as well as blood glucose, BP, lipids
and cigarette smoking. However, there have been few
reports relating sex to the incidence/prevalence and
the pathological condition of microvascular complications. There have been a few studies regarding sex as
a risk factor for nephropathy, with different results.
In a German study of type 1 diabetes mellitus patients,
male sex was a risk factor for evident nephropathy
[37]. In a study of UKPDS, male sex was a risk
factor of an evident albumin urocrisis [38]. In the
report of Takane
, the time when diabetes mellitus and nephropathy were diagnosed tended to be
earlier in men than in women, and the dialysis induction age was significantly lower in men [39]. Daniels
. showed that female sex associated with an
increased frequency of microalbuminuria in children
and adolescents with type 1 diabetes mellitus [40]. In
this study, the rate of remission/regression of
microalbuminuria was significantly higher in female
patients. Future studies investigating sex-specific
interventions to reduce the incidence and rate of progression of diabetic nephropathy are required.
Potential limitations still remain in our study.
First, the definition of regression of microalbuminuria is not generally recognized. We defined regression
of microalbuminuria as a decrease in ACR of ｧ 50ｵ
from baseline, as in the Joslin Diabetes Center study
and Shiga University study [16, 17]. This definition
does not always reflect changes in renal function. It
remains unclear whether a decrease in ACR of ｧ 50
percent reflects improvements in morphological abnormalities. Second, our study did not clarify whether
remission and/or regression of microalbuminuria
finally results in a reduction of the incidence of endstage renal disease (ESRD) or cardiovascular mortality. Because the average observation period was
short, continuation of the observation over the long
term is necessary to confirm the results. Third, we
examined biochemical measurements in spot blood
Acta Med. Okayama　Vol. 68, No. 4
samples, so blood glucose and triglycerides were not
evaluated. Fourth, the small sample size made it difficult to prove the factors that are associated with
remission/regression of microalbuminuria, or to
investigate the importance of each clinical practice
recommendation separately.
In conclusion, we revealed the conditions for
improvement of microalbuminuria in patients with type
2 diabetes mellitus at a typical Japanese clinic. These
results suggest that management of blood glucose and
BP are beneficial and useful measures for the remission and/or regression of microalbuminuria. Lipid
profiles, especially higher level of HDL cholesterol,
might also be important for remission/regression of
microalbuminuria. In addition, the possibility of sexspecific interventions to reduce the incidence and rate
of progression of diabetic nephropathy was suggested.
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